Immunobiological activities of synthetic lipid A analogs with low endotoxicity

Shozo Kotani, Haruhiko Takada, Ichiro Takahashi, Tomohiko Ogawa, Masachika Tsujimoto, Hidetoshi Shimauchi, Takako Ikeda, Haruki Okamura, Toshihide Tamura, Kazuhiro Harada, Shigenori Tanaka, Tetsuo Shiba, Shoichi Kusumoto, Tetsuo Shimamoto

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Synthetic lipid A analogs, β(1-6)glucosamine disaccharide 1,4'-bisphosphates, which possesses four tetradecanoyl groups at the 2- and 2'-amino, and 3- and 3'-hydroxyl groups (LA-17-PP), and each two of the (R)-3-hydroxytetradecanoyl and tetradecanoyl groups at the 2- and 2'-amino and 3- and 3'-hydroxyl groups, respectively (LA-18-PP), were far less endotoxic than synthetic (506, LA-15-PP) and bacterial Escherichia coli type lipid A's; neither compound showed any detectable lethal toxicity in chicken embryos or preparatory activity for the local Schwartzman reaction in rabbits. Also both compounds were only weakly pyrogenic and comparably less lethally toxic in galactosamine-loaded mice than the reference synthetic and bacterial lipid A's and a synthetic counterpart to biosynthetic lipid A precursor Ia (406, LA-14-PP). Nevertheless, LA-17-PP and LA-18-PP exhibited definite in vivo immunoadjuvant activity in mice, and the ability to induce a possible tumor necrosis factor and alpha/beta interferon in Mycobacterium bovis BCG and Propionibacterium acnes-primed mice, respectively, although these two activities were weaker than those of the reference lipid A's. 4'-Monophosphate analogs of the above two test compounds exhibited neither endotoxic nor beneficial activities, but they showed remarkable in vitro bioactivities comparable to those of the corresponding biphosphate compounds; the ability to activate the human complement system and the clotting enzyme cascade of horseshoe crab amoebocyte lysate, stimulatory effects on guinea pig and murine peritoneal macrophages, and murine splenocytes.

Original languageEnglish
Pages (from-to)673-682
Number of pages10
JournalInfection and immunity
Volume54
Issue number3
DOIs
Publication statusPublished - 1986

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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